This K99/R00 proposal is submitted for the support, training, and transition of Dr. Graves from a mentored to independent investigator. The proposal is focused on the mechanisms by which methamphetamine might increase the risk of developing Parkinson's disease. Recent epidemiological work has found that methamphetamine use is associated with nearly ~2-3-fold increased risk for Parkinson's disease. In Parkinson's disease, neurons in the substantia nigra pars compacta, which provide dopamine to the basal ganglia, progressively degenerate. The loss of these neurons is responsible for the cardinal motor symptoms of the disease. Published work from the Surmeier lab indicates that Cav1.3 L-type calcium channel activity in these neurons during pacemaking drives degeneration by increasing mitochondrial oxidant stress. Preliminary data indicates that chronic methamphetamine administration accelerates pacemaking frequency, potentially leading to increased Cav1.3 activity and elevated mitochondrial oxidant stress. Additionally, methamphetamine appears to cause elevations in oxidant stress in dopaminergic nerve terminals due to activity-independent monoamine release and dopamine metabolism by monoamine oxidase-B. Elevation in dopamine metabolism is hypothesized to lead to increased metabolites that can be damaging to the cells and thus increase oxidant stress at terminals and dendritic fields. The final topic of the proposal pursues reports that methamphetamine use increases ?-synuclein pathology, a hallmark of Parkinson's disease. We hypothesize that methamphetamine- induced stress is necessary for the development of ?-synuclein pathology. Accordingly, we propose four Specific Aims to be conducted in mice. The training program detailed in the proposal will expand and advance Dr. Graves' career objective of becoming an independent academic neuroscientist. K99 Aim I: To determine if acute methamphetamine will increase terminal/dendritic mitochondrial stress and chronic methamphetamine will increase activity-dependent somatodendritic mitochondrial stress. K99 Aim II: To determine if chronic methamphetamine will induce ?-synuclein pathology. R00 Aim III: To determine if methamphetamine- induced oxidant stress is attributable to dopamine metabolism by monoamine oxidase-B. R00 Aim IV: To determine if monoamine oxidase-B and Cav1.3 Ca2+ channel activity is necessary for ?-synuclein aggregation. The training program detailed in the proposal will expand and advance Dr. Graves' career objective of becoming an independent academic neuroscientist.